Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

Peng, Feng; Chen, Yonggang; Chen, Cheng‐yi; Dormer, Peter G.; Kassim, Amude M.; McLaughlin, Mark; Reamer, Robert A.; Williamson, R. Thomas; Song, Zhiguo J.; Tan, Lushi; Tudge, Matthew T.; Wan, Baoqiang; Chung, John Y. L.

doi:10.1021/acs.joc.7b01467

Cited by 15 publications

(13 citation statements)

References 23 publications

(24 reference statements)

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“…The second alphabetically was omarigliptin ( 39 ), which was developed by Merck and had its first launch in Japan. The synthesis of this agent was described in detail in 2017 by scientists from WuXi and makes interesting reading as to the use of a “one-pot” system at one stage, which when coupled to a crystallization process gave excellent ee results . The last of the 2015 agents in this category was trelagliptin ( 40 ), which was approved in Japan.…”

Section: Full Discussion Of Resultsmentioning

confidence: 99%

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

Newman¹,

Cragg²

2020

J. Nat. Prod.

3,541

2,843

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For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/ or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.

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Section: Full Discussion Of Resultsmentioning

confidence: 99%

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

Newman¹,

Cragg²

2020

J. Nat. Prod.

3,541

2,843

View full text Add to dashboard Cite

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“…Merck and WuXi AppTec researchers jointly published asymmetric synthesis of dipeptidyl peptidase‐4 (DPP‐4) inhibitor omarigliptin, featuring a base‐mediated CIDT as one of key steps (Scheme 12). [62] Dihydropyran intermediate 28 was obtained as a diastereomeric mixture with trans / cis ratio ca 6:4. A survey of 14 bases helped to identify DABCO as superior in terms of epimerization rate and product stability.…”

Section: Examples Of Cidtmentioning

confidence: 99%

State of the Art in Crystallization‐Induced Diastereomer Transformations

Kolarovič

Jakubec

2021

Adv Synth Catal

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Crystallization-induced diastereomer transformations (CIDT) enable isolation of the target compounds in high enantio-and diastereomeric purities and with up to quantitative yields simply by filtration. Numerous inspiring examples of this appealing synthetic strategy reported over the last fifteen years are reviewed. Important observations along with aspects to consider when designing CIDT experiments are discussed. 3.3. Formation of Schiff Base or Related Intermediates 3.4. Aza-Michael and Mannich-Type Reactions 3.5. Strecker Reaction 3.6. Aldol Reactions 3.7. Epimerization at Phosphorus-Based Stereocenters 3.8. Racemization/Epimerization through Change of Conformation 3.9. Miscellaneous Examples of CIDT 4.Conclusions and Perspectives

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“…As such, a regioselective bromination of phenol 5 provides para -bromoisopropylphenol 6 in high yield. Cu-catalyzed methoxylation (formally an Ullmann methyl aryl ether synthesis) provides our desired phenol in about 75% yield . In addition, these two steps could be telescoped in a one-pot process .…”

Section: Results and Discussionmentioning

confidence: 99%

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Peng

Humphrey

Maloney

et al. 2020

Org. Process Res. Dev.

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Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.

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Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

Cited by 15 publications

References 23 publications

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

State of the Art in Crystallization‐Induced Diastereomer Transformations

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

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